**7. Smart stimulus-responsive nanoparticles in antimicrobial photodynamic therapy**

Further enhancement of selectivity for the disease over host tissue cells can be achieved if the aPDT toxicity of the drug and PS molecules is controlled in such a way that they are only toxic on target and are benign elsewhere. As a result, substantial research has been dedicated to developing stimulus-responsive aPDT. Two approaches have emerged to achieve this. In the one approach, nanoconjugate systems have been

#### *Important Advances in Antibacterial Nanoparticle-Mediated Photodynamic Therapy DOI: http://dx.doi.org/10.5772/intechopen.113340*

cleverly designed and fabricated to respond to the pH and redox potential difference between normal host tissue cells and the extracellular environment, on the one hand, and the intracellular environment of bacterial disease cells, on the other hand. In bacterial cells and the extracellular bacterial microenvironment, the pH drops by nearly 2–3 compared to normal host tissue cells and the usual host tissue extracellular microenvironment [82]. Therefore, systems have been cleverly designed in which the drug and PS molecules are covalently bound by functional groups that are cleaved upon the pH drop as they enter the disease cells. Due to the pH differential, this stimulus responsiveness selects only disease cells to deliver their drug and PS cargo and withholds it anywhere else.

Utilizing the pH differential, the PS curcumin was incorporated into the zeolitic imidazolate framework-8, ZIF-8, which disassembles at low pH, releasing the PS. The zinc ions released from the MOF increased the porousness of the bacterial cell membrane, causing the enhanced production of ROS in the extracellular environment, which resulted in bacterial cell membrane disruption and damaged appearance of the bacteria under the electron microscope [83]. Therefore, the authors concluded that pH-sensitive MOF-mediated bacterial cell targeting might be a promising aPDT strategy. A similar study showed pH-responsive delivery of ammonium methylbenzene blue incorporated into the ZIF-8 [82]. Clearly, the MOF strategy is an important approach to pH-sensitive drugs and PS release in aPDT. The technology of encapsulation of the PS in organic NPs has also been studied in pH-responsive targeting. For example, Chlorin e6-encapsulated pH-sensitive charge-conversion polymeric NPs were used to target *E. coli* infection in low pH urinary tract environments, with more than two-fold efficacy enhancement [84]. Additionally, liposomal encapsulation of PSs can be tuned to be pH-sensitive by formulation of the composition of the phospholipids that form the liposomal bilayer. For example, encapsulation of Chlorin-e6 into pH-sensitive liposomes fabricated by varying the composition of dipalmitoyl phosphatidylcholine, cholesterol, and dimethyl dioctadecyl ammonium chloride in chloroform resulted in selective penetration into the cytoplasm of *E. coli* [85].

Nanoconjugate systems have also been designed that respond to externally applied physical stimuli, such as MH, PTT, and US. The high preference for MH and ultrasound (US) is due to their unlimited tissue penetration depth compared to the limited tissue penetration depth of light, even in the therapeutic window. Utilizing external stimuli may be illustrated with the combination of MH with PDT by encapsulating magnetic iron oxide NPs in the liposome aqueous core and organic PSs in the hydrophobic liposomal bilayer (**Figure 9a**). The PS is released upon applying a high frequency alternating magnetic field (**Figure 9b**), which elevates the temperature to 42–45°C, disassembling the liposome and releasing the PS (**Figure 9c**) from the liposomal bilayer [86]. Encapsulating plasmonic and photo-responsive NPs also achieves the release of the PS in the same way, upon the application of light to elevate the temperature by the photothermal mechanism. Used to target cancer cells in experimental studies, this approach eradicated all cancer cells in an *in vitro* study and completely ablated the solid tumors *in vivo* [87].

Interestingly, to the best of our literature search, studies of MH in combination with PDT have not been reported, although studies on the antibacterial effects of static magnetic fields have been conducted. For example, applying an external magnetic field caused magnetic NPs to move deep into the biofilm [88]. Yet no studies have been found on the application of MH in combination with PDT to eradicate bacteria. Liposomal encapsulation of plasmonic NPs and PSs as a basis for antibacterial photothermal and aPDT combination, on the other hand, has been reported. The encapsulation of gold nanorods in the liposome core and the PS curcumin in

**Figure 9.** *Magnetic hyperthermia-triggered release of the PS from the liposome bilayer.*

the liposome bilayer, for example, was reported for treating recurrent acne with the combination of PTT and aPDT [89]. In this research, the curcumin PS is activated by blue light for PDT, while the gold nanorods were activated by near infrared (NIR) light for PTT, resulting in heat and ROS-based inhibition of bacterial growth.
